To determine the role of testosterone on liver fat deposition using the testicular feminised mouse (Tfm) model. The Tfm does not have a functional androgen receptor (AR) and low circulating levels of testosterone due to associated 17αhydroxylase deficiency.
Liver tissue was obtained after 24 weeks of feeding with a cholesterol enriched diet from the following groups: (1) XY placebo-treated (littermate control), (2) Tfm placebo, (3) XY castrate placebo, (4) Tfm sham operated, (5) Tfm treated with physiological (Sustanon 100) and (6) Tfm supraphysiological (Sustanon 250) testosterone replacement therapy (TRT) and (7) Tfm with physiological TRT and Faslodex (α-oestradiol antagonist). Liver sections were stained with Oil Red O dye and analysed for staining intensity using Image J 1.40 g software (mean of 25 sections per group).
Tfm placebo liver (173.97±4.89) had greater fat content than XY placebo (139.65±6.27; P<0.0001). XY Castrates had higher liver fat composition (157.55±10.02) than XY placebo (P<0.0001). Tfm physiological TRT (166.11±5.83) had a lower mean red intensity than Tfm placebo (P<0.0001). Supraphysiological levels of TRT had the lowest fat content (96.17±17.97) which was statistically significant when compared to Tfm placebo (P<0.0001), and Tfm (S100; P<0.0001). Tfm S100-treated which were co-administered with Faslodex (162.59±8.45) were compared with Tfm S100 was not statistically significant (P=0.094).
These results have demonstrated that that testosterone deficiency promotes the development of liver steatosis. Testosterone therapy improves steatosis through a mechanism which is independent of the androgen receptor. This effect is not mediated through the α-oestradiol receptor. We have reported a similar effect in the development of aortic root lipid streak formation in this model1. Testosterone is known to inhibit adipocyte lipoprotein lipase activity hence reducing free fatty acid uptake and triglyceride storage. The exact mechanism by which testosterone inhibits liver fat accumulation using the tfm mouse model is under investigation.
Reference: 1. Nettleship JE et al. Circulation 2007 116 24272434.